The present invention relates to inhibitors of protein kinase, especially c-Jun N-terminal kinases (JNK) and the Src-family of kinases, including Lck, which are members of the mitogen-activated protein (MAP) kinase family. JNK, Src, and Lck have been implicated in a number of different human diseases. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders in which JNK, Src, and Lck play a role.
Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which include the extracellular signal regulated kinases (ERKs), the p38 MAP kinases and the c-Jun N-terminal kinases (JNKs). MAP kinases (MAPKs) are activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents. MAPKs are serine/threonine kinases and their activation occur by dual phosphorylation of threonine and tyrosine at the Thr-X-Tyr segment in the activation loop. MAPKs phosphorylate various substrates including transcription factors, which in turn regulate the expression of specific sets of genes and thus mediate a specific response to the stimulus.
One particularly interesting kinase family are the c-Jun NH2-terminal protein kinases, also known as JNKs. Three distinct genes, JNK1, JNK2, JNK3 have been identified and at least ten different splicing isoforms of JNKs exist in mammalian cells [Gupta et al., EMBO J., 15:2760-70 (1996)]. Members of the JNK family are activated by proinflammatory cytokines, such as tumor necrosis factor-xcex1 (TNFxcex1) and interleukin-1 xcex2 (IL-1xcex2), as well as by environmental stress, including anisomycin, UW irradiation, hypoxia, and osmotic shock [Minden et al., Biochemica et Biophysica Acta, 1333:F85-F104 (1997)].
The down-Stream substrates of JNKs include transcription factors c-Jun, ATF-2, Elk1, p53 and a cell death domain protein (DENN) [Zhang et al. Proc. Natl. Acad. Sci. USA, 95:2586-91 (1998)]. Each JNK isoform binds to these substrates with different affinities, suggesting a regulation of signaling pathways by substrate specificity of different JNKs in vivo (Gupta et al., supra).
JNKs, along with other MAPKs, have been implicated in having a role in mediating cellular response to cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. The therapeutic targets related to activation of the JNK pathway include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases.
Several reports have detailed the importance of JNK activation associated with liver disease or episodes of hepatic ischemia [Nat. Genet. 21:326-9 (1999); FEBS Lett. 420:201-4 (1997); J. Clin. Invest. 102:1942-50 (1998); Hepatology 28:1022-30 (1998)]. Therefore, inhibitors of JNK may be useful to treat various hepatic disorders.
A role for JNK in cardiovascular disease such as myocardial infarction or congestive heart failure has also been reported as it has been shown JNK mediates hypertrophic responses to various forms of cardiac stress [Circ. Res. 83:167-78 (1998); Circulation 97:1731-7 (1998); J. Biol. Chem. 272:28050-6 (1997); Circ. Res. 79:162-73 (1996); Circ. Res. 78:947-53 (1996); J. Clin. Invest. 97:508-14 (1996)].
It has been demonstrated that the JNK cascade also plays a role in T-Cell activation, including activation of the IL-2 promoter. Thus, inhibitors of JNK may have therapeutic value in altering pathologic immune responses [J. Immunol. 162:3176-87 (1999); Eur. J. Immunol. 28:3867-77 (1998); J. Exp. Med. 186:941-53 (1997); Eur. J. Immunol. 26:989-94 (1996)].
A role for JNK activation in various cancers has also been established, suggesting the potential use of JNK inhibitors in cancer. For example, constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis [Oncogene 13:135-42 (1996)]. JNK may play a role in Kaposi""s sarcoma (KS) because it is thought that the proliferative effects of bFGF and OSM on KS cells are mediated by their activation of the JNK signaling pathway [J. Clin. Invest. 99:1798-804 (1997)]. Other proliferative effects of other cytokines implicated in KS proliferation, such as vascular endothelial growth factor (VEGF), IL-6 and TNFxcex1, may also be mediated by JNK. In addition, regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, suggesting a role for JNK inhibitors in the treatment for chronic myelogenous leukemia (CML) [Blood 92:2450-60 (1998)].
JNK1 and JNK2 are widely expressed in a variety of tissues. In contrast, JNK3, is selectively expressed in the brain and to a lesser extent in the heart and testis [Gupta et al., supra; Mohit et al., Neuron 14:67-78 (1995); Martin et al., Brain Res. Mol. Brain Res. 35:47-57 (1996)]. JNK3 has been linked to neuronal apoptosis induced by kainic acid, indicating a role of JNK in the pathogenesis of glutamate neurotoxicity. In the adult human brain, JNK3 expression is localized to a subpopulation of pyramidal neurons in the CA1, CA4 and subiculum regions of the hippocampus and layers 3 and 5 of the neocortex [Mohit et al., supra]. The CA1 neurons of patients with acute hypoxia showed strong nuclear JNK3-immunoreactivity compared to minimal, diffuse cytoplasmic staining of the hippocampal neurons from brain tissues of normal patients [Zhang et al., supra]. Thus, JNK3 appears to be involved involved in hypoxic and ischemic damage of CA1 neurons in the hippocampus.
In addition, JNK3 co-localizes immunochemically with neurons vulnerable in Alzheimer""s disease [Mohit et al., supra]. Disruption of the LNK3 gene caused resistance of mice to the excitotoxic glutamate receptor agonist kainic acid, including the effects on seizure activity, AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the JNK3 signaling pathway is a critical component in the pathogenesis of glutamate neurotoxicity (Yang et al., Nature, 389:865-870 (1997)].
Based on these findings, JNK signalling, especially that of JNK3, has been implicated in the areas of apoptosis-driven neurodegenerative diseases such as Alzheimer""s Disease, Parkinson""s Disease, ALS (Amyotrophic Lateral Sclerosis), epilepsy and seizures, Huntington""s Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke.
The Src-family of kinases are implicated in cancer, immune system dysfunction, and bone remodeling diseases. For general reviews, see Thomas and Brugge, Annu. Rev. Cell Dev. Biol. (1997) 13, 513; Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49; Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
Members of the Src family include the following eight kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, Blk and Yrc. These are nonreceptor protein kinases that range in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinct functional domains: Src homology domain 4 (SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain (SH1), and a C-terminal regulatory region. Tatosyan et al. Biochemistry (Moscow) 65, 49-58 (2000).
Based on published studies, Src kinases are considered as potential therapeutic targets for various human diseases. Mice that are deficient in Src develop osteopetrosis, or bone build-up, because of depressed bone resorption by osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption can be treated by inhibiting Src. Soriano et al., Cell, 69, 551 (1992) and Soriano et al., Cell, 64, 693 (1991).
Suppression of arthritic bone destruction has been achieved by the overexpression of CSK in rheumatoid synoviocytes and osteoclasts. Takayanagi et al., J. Clin. Invest., 104, 137 (1999). CSK, or C-terminal Src kinase, phosphorylates and thereby inhibits Src catalytic activity. This implies that Src inhibition may prevent joint destruction that is characteristic in patients suffering from rheumatoid arthritis. Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
Src also plays a role in the replication of hepatitis B virus. The virally encoded transcription factor HBx activates Src in a step required for propagation of the virus. Klein et al., EMBO J., 18, 5019, (1999) and Klein et al., Mol. Cell. Biol., 17, 6427 (1997).
A number of studies have linked Src expression to cancers such as colon, breast, hepatic and pancreatic cancer, certain B-Cell leukemias and lymphomas. Talamonti et al., J. Clin. Invest., 91, 53 (1993); Lutz et al., Biochem. Biophys. Res. 243, 503 (1998); Rosen et al., J. Biol. Chem., 261, 13754 (1986); Bolen et al., Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki et al., Hepatology, 27, 1257 (1998); Biscardi et al., Adv. Cancer Res., 76, 61 (1999); Lynch et al., Leukemia, 7, 1416 (1993). Furthermore, antisense Src expressed in ovarian and colon tumor cells has been shown to inhibit tumor growth. Wiener et al., Clin. Cancer Res., 5, 2164 (1999); Staley et al., Cell Growth Diff., 8, 269 (1997).
Other Src family kinases are also potential therapeutic targets. Lck plays a role in T-Cell signaling. Mice that lack the Lck gene have a poor ability to develop thymocytes. The function of Lck as a positive activator of T-Cell signaling suggests that Lck inhibitors may be useful for treating autoimmune disease such as rheumatoid arthritis. Molina et al., Nature, 357, 161 (1992). Hck, Fgr and Lyn have been identified as important mediators of integrin signaling in myeloid leukocytes. Lowell et al., J. Leukoc. Biol., 65, 313 (1999). Inhibition of these kinase mediators may therefore be useful for treating inflammation. Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
Accordingly, there is still a great need to develop potent inhibitors of JNKs and Src family kinases that are useful in treating various conditions associated with JNK and Src activation.
The present invention provides compounds of formula I: 
wherein R1, R2, R3, R4, and Ra are as described below.
The present invention also provides a pharmaceutical composition comprising a compound of formula I.
The compounds and pharmaceutical compositions of the present invention are useful as inhibitors of c-Jun N-terminal kinases (JNK) and Src family kinases, including Src and Lck. Thus, they are also useful in methods for treating or preventing a variety of disorders, such as heart disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases. The compositions are also useful in methods for preventing cell death and hyperplasia and therefore may be used to treat or prevent reperfusion/ischemia in stroke, heart attacks, and organ hypoxia. The compositions are also useful in methods for preventing thrombin-induced platelet aggregation. The compositions are especially useful for disorders such as chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, liver disease including hepatic ischemia, heart disease such as myocardial infarction and congestive heart failure, pathologic immune conditions involving T cell activation and neurodegenerative disorders.
The present invention provides a compound of formula I: 
or a pharmaceutically acceptable derivative thereof, wherein:
A and B are each independently selected from N or CH;
R1 and R2 are each independently selected from halogen, CN, NO2, N(R)2, OR, SR, or (T)nxe2x80x94R5;
R3 is selected from a 3-6 membered carbocyclic or heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said phenyl or heteroaryl ring is optionally substituted with one (T)nxe2x80x94Ar and one to two R7;
each n is independently selected from zero or one;
T is a C1-C6 alkylidene chain, wherein one methylene unit of T is optionally replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR;
each R is independently selected from hydrogen or an optionally substituted C1-C6 aliphatic group; or two R on the same nitrogen atom may be taken together with the nitrogen to form a four to eight membered, saturated or unsaturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4 is (T)nxe2x80x94R, (T)nxe2x80x94Ar, or (T)nxe2x80x94Ar1;
Ra is selected from Rb, halogen, NO2, ORb, SRb, or N(Rb)2;
Rb is selected from hydrogen or a C1-C4 aliphatic group optionally substituted with oxo, OH, SH, NH2, halogen, NO2, or CN;
R5 is an optionally substituted C1-C6 aliphatic or Ar;
Ar is a 5-6 membered saturated, partially unsaturated, or aryl monocyclic ring having zero to three heteroatoms independently selected from nitrogen, sulfur, or oxygen, or an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having zero to four heteroatoms independently selected from nitrogen, sulfuri or oxygen, wherein Ar is optionally substituted with one to three R7;
Ar1 is a 6-membered aryl ring having zero to two nitrogens, wherein said ring is substituted with one Zxe2x80x94R6 group and optionally substituted with one to three R7;
Z is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Z are optionally replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR; provided that said optionally replaced methylene unit of Z is a methylene unit non-adjacent to R6;
R6 is selected from Ar, R, halogen, NO2, CN, OR, SR, N(R)2, NRC(O)R, NRC(O)N(R)2, NRCO2R, C(O)R, CO2R, OC(O)R, C(O)N(R)2, OC(O)N(R)2, SOR, SO2R, SO2N(R)2, NRSO2R, NRSO2N(R)2, C(O)C(O)R, or C(O)CH2C(O)R; and
each R7 is independently selected from R, halogen, NO2, CN, OR, SR, N(R)2, NRC(O)R, NRC(O)N(R)2, NRCO2R, C(O)R, CO2R, C(O)N(R)2, OC(O)N(R)2, SOR, SO2R, SO2N(R)2, NRSO2R, NRSO2N(R)2, C(O)C(O)R, or C(O)CH2C(O)R; or two R7 on adjacent positions of Ar1 may be taken together to form a saturated, partially unsaturated, or fully unsaturated five to seven membered ring containing zero to three heteroatoms selected from O, S, or N.
The following abbreviations are used throughout the specifications (including in chemical formulae):
iPr=isopropyl
t-Bu or tBu=tert-butyl
Et=ethyl
Me=methyl
Cbz=benzoyloxycarbonyl
BOC=tert-butyloxycarbonyl
Ph=phenyl
Bn=benzyl
DMF=N,N-dimethylformamide
THF=tetrahydrofuran
DCM=dichloromethane
DMF-DMA=N,N-dimethylformamide-dimethylacetal
DMSO-dimethylsulfoxide
TLC=thin layer chromatography
As used herein, the following definitions shall apply unless otherwise indicated.
The phrase xe2x80x9coptionally substitutedxe2x80x9d is used interchangeably with the phrase xe2x80x9csubstituted or unsubstitutedxe2x80x9d or with the term xe2x80x9c(un)substituted.xe2x80x9d Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term xe2x80x9caliphaticxe2x80x9d or xe2x80x9caliphatic groupxe2x80x9d as used herein means a straight-chain or branched C1-C12 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
The terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, and xe2x80x9calkoxycarbonylxe2x80x9d, used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms.
The terms xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkenylxe2x80x9d and xe2x80x9chaloalkoxyxe2x80x9d means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term xe2x80x9chalogenxe2x80x9d means F, Cl, Br, or I.
The term xe2x80x9cheteroatomxe2x80x9d means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term xe2x80x9cnitrogenxe2x80x9d includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-Substituted pyrrolidinyl).
The term xe2x80x9carylxe2x80x9d used alone or as part of a larger moiety as in xe2x80x9caralkylxe2x80x9d, xe2x80x9caralkoxyxe2x80x9d, or xe2x80x9caryloxyalkylxe2x80x9d, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term xe2x80x9carylxe2x80x9d may be used interchangeably with the term xe2x80x9caryl ringxe2x80x9d. The term xe2x80x9carylxe2x80x9d also refers to heteroaryl ring systems as defined hereinbelow.
The term xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, or xe2x80x9cheterocyclicxe2x80x9d as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members.
The term xe2x80x9cheteroarylxe2x80x9d, used alone or as part of a larger moiety as in xe2x80x9cheteroaralkylxe2x80x9d or xe2x80x9cheteroarylalkoxyxe2x80x9d, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term xe2x80x9cheteroarylxe2x80x9d may be used interchangeably with the term xe2x80x9cheteroaryl ringxe2x80x9d or the term xe2x80x9cheteroaromaticxe2x80x9d.
An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, xe2x80x94Rxc2x0, xe2x80x94ORxc2x0, xe2x80x94SRxc2x0, 1,2-methylene-dioxy, 1,2-ethylenedioxy, phenyl (Ph) optionally substituted with Rxc2x0, xe2x80x94O(Ph) optionally substituted with Rxc2x0, xe2x80x94CH2(Ph) optionally substituted with Rxc2x0, xe2x80x94CH2CH2(Ph), optionally substituted with Rxc2x0, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(Rxc2x0)2, xe2x80x94NRxc2x0C(O)Rxc2x0, xe2x80x94NRxc2x0C(O)N(Rxc2x0)2, xe2x80x94NRxc2x0CO2Rxc2x0, xe2x80x94NRxc2x0NRxc2x0C(O)Rxc2x0, xe2x80x94NRxc2x0NRxc2x0C(O)N(Rxc2x0)2, xe2x80x94NRxc2x0NRxc2x0CO2Rxc2x0, xe2x80x94C(O)C(O)Rxc2x0, xe2x80x94C(O)CH2C(O)Rxc2x0, xe2x80x94CO2Rxc2x0, xe2x80x94C(O)Rxc2x0, xe2x80x94C(O)N(Rxc2x0)2, xe2x80x94OC(O)N(Rxc2x0)2, xe2x80x94S(O)2Rxc2x0, xe2x80x94SO2N(Rxc2x0)2, xe2x80x94S(O)Rxc2x0, xe2x80x94NRxc2x0SO2N(Rxc2x0)2, xe2x80x94NRxc2x0SO2Rxc2x0, xe2x80x94C(xe2x95x90S)N(Rxc2x0)2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(Rxc2x0)2, or xe2x80x94(CH2)yNHC(O)Rxc2x0, wherein each Rxc2x0 is independently selected from hydrogen, optionally substituted C1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, xe2x80x94O(Ph), or xe2x80x94CH2(Ph). Optional substituents on the aliphatic group of Rxc2x0 are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, O(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O(halo C1-4 aliphatic), or halo C1-4 aliphatic.
An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: xe2x95x90O, xe2x95x90S, xe2x95x90NNHR*, xe2x95x90NN(R*)2, xe2x95x90NNHC(O)R*, xe2x95x90NNHCO2(alkyl), xe2x95x90NNHSO2(alkyl), or xe2x95x90NR*, where each R* is independently selected from hydrogen or an optionally substituted C1-6 aliphatic. Optional substituents on the aliphatic group of R* are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, O(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O(halo C1-4 aliphatic), or halo(C1-4 aliphatic).
Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from xe2x80x94R+, xe2x80x94N(R+)2, xe2x80x94C(O)R+, xe2x80x94CO2R+, xe2x80x94C(O)C(O)R+, xe2x80x94C(O)CH2C(O)R+, xe2x80x94SO2R+, xe2x80x94SO2N(R+)2, xe2x80x94C(xe2x95x90S)N(R+)2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R+)2, or xe2x80x94NR+SO2R+; wherein R+ is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted xe2x80x94O(Ph), optionally substituted xe2x80x94CH2(Ph), optionally substituted-CH2CH2(Ph), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, O(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O(halo C1-4 aliphatic), or halo(C1-4 aliphatic).
The term xe2x80x9calkylidene chainxe2x80x9d refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation.
A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
Preferred R1 groups of formula I are selected from N(R)2, OR, SR, or (T)nxe2x80x94R5 wherein T is a C1-4 alkylidene chain and wherein one methylene unit of T is optionally replaced by S, O, N(R), or CO2. More preferred RI groups of formula I are selected from SCH2-4-phenol, SCH3, OH, OEt, N(Me)2, OMe, 4-methylpiperidin-1-yl, NHEt, NHCH2CH2piperidin-1-yl, or NHCH2CH2morpholin-4-yl.
Preferred R2 groups of formula I are selected from CN, R5, halogen, CO2R5, or N(R)2. More preferred R2 groups are selected from CN or CO2R5.
Preferred R3 groups of formula I are selected from 5-6 membered ring selected from carbocyclic, phenyl, or a heterocyclyl or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R3 is optionally substituted with one (T)nxe2x80x94Ar group and one R7. More preferred R3 groups of formula I are selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, and furanyl. Preferred substituents on R3 are selected from (T)nxe2x80x94Ar or R7 wherein Ar is a an optionally substituted 5-6 membered aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R7 is selected from R, halogen, OR, N(R)2, or CO2R. More preferred substituents on R3 are selected from phenyl, phenoxy, benzyl, benzyloxy, pyridyl, 3-hydroxyphenyl, 2 -hydroxyphenyl, 3-aminophenyl, N-BOC-pyrrolyl, 4-chlorophenyl, 3-ethoxypyridyl, 2-methoxypyridyl, 2,5-dimethylisoxazolyl, 3-ethoxyphenyl, 4-isopropylphenyl, 4-F-3-Cl-phenyl, pyrrolyl, pyrimidinyl, halogen, such as chloro, bromo, and fluoro, haloalkyl such as trifluoromethyl, OH, NH2, alkyl, such as methyl, and alkoxy, such as methoxy and ethoxy.
Preferred R4 groups of formula I are selected from hydrogen or Ar wherein Ar is an optionally substituted 6 membered saturated, partially saturated, or aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred R4 groups of formula I are selected from phenyl, benzyl, pyridyl, piperidinyl, and cyclohexyl. Preferred substituents on R4 are selected from CO2R, OR, OAr, halogen, NRSO2R, SO2N(R)2, NRCON(R)2, NO2, or N(R)2. More preferred substituents of R4 are selected from benzyloxy, phenoxy, SO2NH2, OH, NO2, NH2, OMe, Br, Cl, CO2Me, NHSO2Me, NHSO2Et, NHCON(Me)2, NHCON(Et)2, NHCOpyrrolidin-1-yl, or NHCOmorpholin-4-yl.
Most preferred R4 groups of formula I are those wherein R4 is Ar1. Preferred Zxe2x80x94R6 groups of the Ar1 group of formula I are those wherein Z is a C1-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, NH, NHCO, NHCO2, NHSO2, CONH, and wherein R6 is selected from N(R)2, NHCOR, or Ar wherein Ar is a 5-6 membered heterocyclic or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. The Ar group of R6 is optionally substituted with R, OR, N(R)2, or oxo. More preferred Zxe2x80x94R6 groups of formula I are selected from O(CH2)3OH, O(CH2)3NH(CH2)2OH, O(CH2)2NH(CH2)2OH, O(CH2)3N(hydroxyethyl) (methyl), O(CH2)3pyrrolidin-1-yl, O(CH2)2morpholin-4-yl, O(CH2)3N(Me)2, O(CH2)3N(Et)2, O(CH2)3 (4-hydroxyethylpiperazin-1-yl), O(CH2)3piperazin-1-yl,O(CH2)3(4-hydroxymethylpiperidin-1-yl), O(CH2)3(4-hydroxypiperidin-1-yl), NHCO(CH2)3N(Me)2, NHCO(CH2)3NCOCH3, NHCOCH2pyridin-2-yl, NHCOCH2(2-aminothiazol-4-yl), NHCOCH2cyclopropyl, NHCO(CH2)2N(Et)2, NHCO(CH2)2(piperazin-2,5-dione-3-yl), NHCOpyrrolidin-1-yl, NHCOmorpholin-4-yl, NHCO2CH2tetrahydrofuran-2-yl, NHCO2tetrahydrofuran-2-yl, NHCO2tetrahydropyran-4-yl, or NHCO2CH2tetrahydropyran-2-yl.
Preferred Ra groups of formula I are selected from Rb, ORb, SRb, or N (Rb)2. More preferred Ra groups of formula I are selected from methyl, OH, OMe, or NH2.
One embodiment of this invention relates to compounds of formula IIa: 
or a pharmaceutically acceptable derivative thereof, wherein R1, R2, R3, and R4 are as described above.
Preferred R1 groups of formula IIa are selected from N(R)2, OR, SR, or (T)nxe2x80x94R5 wherein T is a C1-4 alkylidene chain and wherein one methylene unit of T is optionally replaced by S, O, N(R), or CO2. More preferred R1 groups of formula IIa are selected from SCH2-4-phenol, SCH3, OH, OEt, N(Me)2, OMe, 4-methylpiperidin-1-yl, NHEt, NHCH2CH2piperidin-1-yl, or NHCH2CH2morpholin-4-yl.
Preferred R2 groups of formula IIa are selected from CN, R5, halogen, CO2R5, or N(R)2. More preferred R2 groups are selected from CN or CO2R5.
Preferred R3 groups of formula IIa are selected from 5-6 membered ring selected from carbocyclic, phenyl, or a heterocyclyl or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R3 is optionally substituted with one (T)nxe2x80x94Ar group and one R7. More preferred R3 groups of formula IIa are selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, and furanyl. Preferred substituents on R3 are selected from (T)nxe2x80x94Ar or R7 wherein Ar is a an optionally substituted 5-6 membered aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R7 is selected from R, halogen, OR, N(R)2, or CO2R. More preferred substituents on R3 are selected from phenyl, phenoxy, benzyl, benzyloxy, pyridyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3-aminophenyl, N-BOC-pyrrolyl, 4-chlorophenyl, 3-ethoxypyridyl, 2-methoxypyridyl, 2,5-dimethylisoxazolyl, 3-ethoxyphenyl, 4-isopropylphenyl, 4-F-3-Cl-phenyl, pyrrolyl, pyrimidinyl, halogen, such as chloro, bromo, and fluoro, haloalkyl such as trifluoromethyl, OH, NH2, alkyl, such as methyl, and alkoxy, such as methoxy and ethoxy.
Preferred R4 groups of formula IIa are selected from hydrogen or Ar wherein Ar is an optionally substituted 6 membered saturated, partially saturated, or aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred R4 groups of formula IIa are selected from phenyl, benzyl, pyridyl, piperidinyl, and cyclohexyl. Preferred substituents on R4 are selected from CO2R, OR, OAr, halogen, NRSO2R, SO2N(R)2, NRCON(R)2, NO2, or N(R)2. More preferred substituents of R4 are selected from benzyloxy, phenoxy, SO2NH2, OH, NO2, NH2, OMe, Br, Cl, CO2Me, NHSO2Me, NHSO2Et, NHCON (Me)2, NHCON (Et)2, NHCOpyrrolidin-1-yl, or NHCOmorpholin-4-yl.
Preferred compounds of formula IIa are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R1 is selected from N(R)2, OR, SR, or (T)nxe2x80x94R5;
(b) T is a C1-4 alkylidene chain, wherein one methylene unit of T is optionally replaced by S, O, N(R), or CO2;
(c) R2 is CN, R, halogen, C2R5, or N(R)2;
(d) R3 is a 5-6 membered ring selected from carbocyclic, phenyl, or a heterocyclyl or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R3 is optionally substituted with one (T)nxe2x80x94Ar group and one R7; and
(e) R4 is hydrogen or Ar, wherein Ar is an optionally substituted 6 membered saturated, partially saturated, or aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur.
More preferred compounds of formula IIa are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R1 is selected from SCH2-4-phenol, SCH3, OH, OEt, N(Me)2, OMe, 4-methylpiperidin-1-yl, NHEt, NHCH2CH2piperidin-1-yl, or NHCH2CH2morpholin-4-yl;
(b) R2 is CN or C2R5;
(c) R3 is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, or furanyl, wherein R3 is optionally substituted with phenyl, phenoxy, benzyl, benzyloxy, pyridyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3-aminophenyl, N-BOC-pyrrolyl, 4-chlorophenyl, 3-ethoxypyridyl, 2-methoxypyridyl, 2,5-dimethylisoxazolyl, 3-ethoxyphenyl, 4-isopropylphenyl, 4-F-3-Cl-phenyl, pyrrolyl, pyrimidinyl, chloro, bromo, fluoro, trifluoromethyl, OH, NH2, methyl, methoxy or ethoxy; and
(d) R4 is selected from hydrogen or a phenyl, benzyl, pyridyl, piperidinyl, or cyclohexyl ring, wherein said ring is optionally subsituted with benzyloxy, phenoxy, SO2NH2, OH, NO2, NH2, OMe, Br, Cl, CO2Me, NHSO2Me, NHSO2Et, NHCON(Me)2, NHCON(Et)2, NHCOpyrrolidin-1-yl, or NHCOmorpholin-4-yl.
Another embodiment relates to compounds of formula IIb: 
or a pharmaceutically acceptable derivative thereof, wherein R1, R2, R3, and R4 are as defined above.
Preferred R1, R3, and R4 groups of formula IIb are those described above for compounds of formula IIa.
Preferred R2 groups of formula IIb are CN, R7, Ar, halogen, or N(R6)2. When R2 is Ar, a preferred Ar group is 4-(C1-3 alkyl)-thiazol-2-yl.
Preferred compounds of formula IIb are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R1 is selected from N(R)2, OR, SR, or (T)nxe2x80x94R5;
(b) T is a C1-4 alkylidene chain, wherein one methylene unit of T is optionally replaced by S, O, N(R), or CO2;
(c) R2 is CN, R7, Ar, halogen, or N(R6)2;
(d) R3 is a 5-6 membered ring selected from carbocyclic, phenyl, or a heterocyclyl or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R3 is optionally substituted with one (T)nxe2x80x94Ar group and one R7; and
(e) R4 is hydrogen or Ar, wherein Ar is an optionally substituted 6 membered saturated, partially saturated, or aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur.
More preferred compounds of formula IIb are those having one or more, more preferably more than one, 2and most preferably all, of the features selected from the group consisting of:
(a) R1 is selected from SCH2-4-phenol, SCH3, OH, OEt, N(Me)2, OMe, 4-methylpiperidin-1-yl, NHEt, NHCH2CH2piperidin-1-yl, or NHCH2CH2morpholin-4-yl;
(b) R2 is CN or 4-(C1-3 alkyl)-thiazol-2-yl;
(c) R3 is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, or furanyl, wherein R3 is optionally substituted with phenyl, phenoxy, benzyl, benzyloxy, pyridyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3-aminophenyl, N-BOC-pyrrolyl, 4-chlorophenyl, 3-ethoxypyridyl, 2-methoxypyridyl, 2,5-dimethylisoxazolyl, 3-ethoxyphenyl, 4-isopropylphenyl, 4-F-3-Cl-phenyl, pyrrolyl, pyrimidinyl, chloro, bromo, fluoro, trifluoromethyl, OH, NH2, methyl, methoxy or ethoxy; and
(d) R4 is selected from hydrogen or a phenyl, benzyl, pyridyl, piperidinyl, or cyclohexyl ring, wherein said ring is optionally subsituted with benzyloxy, phenoxy, SO2NH2, OH, NO2, NH2, OMe, Br, Cl, CO2Me, NHSO2Me, NHSO2Et, NHCON(Me)2, NHCON(Et)2, NHCOpyrrolidin-1-yl, or NHCOmorpholin-4-yl.
Exemplary structures of formula IIa are set forth in Table 1 below. 
Exemplary structures of formula IIb are set forth in Table 2 below.
The above formulae IIa and IIb compounds are those having a pyrimidine ring. Compounds of formula I having a pyridine or triazine ring are otherwise structurally similar to the formulae IIa and IIb compounds and are represented by the following general formulae IIIa, IIIb, IVa, and IVb shown below in Table 3.
The compounds shown above in Table 3 are structurally similar to compounds of formula IIa and IIb where the pyrimidine ring of formula IIa is replaced by a pyridine (IIIa and IIIb) or triazine ring (IVa and IVb). Accordingly, preferred R1, R2, R3, and R4 groups of the compounds shown above in Table 3 are as described above for the formula IIa compounds.
Exemplary structures of formulae IIIa and IIIb are set forth in Table 4 below.
Exemplary structures of formulae IVa and IVb are set forth in Table 5 below.
A preferred embodiment of this invention relates to compounds of formula V: 
or a pharmaceutically acceptable derivative thereof, wherein Ra, R1, R2, R3, and R4 are as defined above.
Preferred compounds of formula V include those having one or more, and most preferably all, of the following features:
(a) R1 is selected from N(R)2, OR, SR, or (T)nxe2x80x94R5;
(b) T is a C1-4 alkylidene chain, wherein one methylene unit of T is optionally replaced by S, O, N(R), or CO2;
(c) R2 is CN, R, halogen, C2R5, or N(R)2;
(d) R3 is a 5-6 membered ring selected from carbocyclic, phenyl, or a heterocyclyl or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R3 is optionally substituted with one (T)nxe2x80x94Ar group and one R7;
(e) R4 is hydrogen or Ar, wherein Ar is an optionally substituted 6 membered saturated, partially saturated, or aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
(f) Ra is selected from Rb, ORb, SRb, or N(Rb)2.
More preferred compounds of formula V are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R1 is selected from SCH2-4-phenol, SCH3, OH, OEt, N(Me)2, OMe, 4-methylpiperidin-1-yl, NHEt, NHCH2CH2piperidin-1-yl, or NHCH2CH2morpholin-4-yl;
(b) R2 is CN or C2R5;
(c) R3 is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, or furanyl, wherein R3 is optionally substituted with phenyl, phenoxy, benzyl, benzyloxy, pyridyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3-aminophenyl, N-BOC-pyrrolyl, 4-chlorophenyl, 3-ethoxypyridyl, 2-methoxypyridyl, 2,5-dimethylisoxazolyl, 3-ethoxyphenyl, 4-isopropylphenyl, 4-F-3-Cl-phenyl, pyrrolyl, pyrimidinyl, chloro, bromo, fluoro, trifluoromethyl, OH, NH2, methyl, methoxy or ethoxy;
(d) R4 is selected from hydrogen or a phenyl, benzyl, pyridyl, piperidinyl, or cyclohexyl ring, wherein said ring is optionally subsituted with benzyloxy, phenoxy, SO2NH2, OH, NO2, NH2, OMe, Br, Cl, CO2Me, NHSO2Me, NHSO2Et, NHCON(Me)2, NHCON(Et)2, NHCOpyrrolidin-1-yl, or NHCOmorpholin-4-yl; and
(e) Ra is methyl, OH, OMe, or NH2.
Exemplary structures of formula V, wherein R2 is CN, are set forth in Table 7 below.
A more preferred embodiment relates to compounds of formula VI: 
or a pharmaceutically acceptable derivative thereof, wherein R1, R2, R3, Ra, Z, and R6 are as defined above.
Preferred R1, R2, R3, and Ra groups of formula VI are those described above for formula IIa.
Preferred Zxe2x80x94R6 groups of formula VI are those wherein Z is a C1-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, NH, NHCO, NHCO2, NHSO2, CONH, and wherein R6 is selected from N(R)2, NHCOR, or Ar wherein Ar is a 5-6 membered heterocyclic or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. The Ar group of R6 is optionally substituted with R, OR, N(R)2, or oxo. More preferred Zxe2x80x94R6 groups of formula VI are selected from O(CH2)3OH, O(CH2)3NH(CH2)2OH, O(CH2)2NH(CH2)2OH, O(CH2)3N(hydroxyethyl) (methyl), O(CH2)3pyrrolidin-1-yl, O(CH2)2morpholin-4-yl, O(CH2)3N(Me)2, O(CH2)3N(Et)2, O(CH2)3(4-hydroxyethylpiperazin-1-yl), O(CH2)3piperazin-1-yl, O(CH2)3(4-hydroxymethylpiperidin-1-yl), O(CH2)3(4-hydroxypiperidin-1-yl), NHCO(CH2)3N(Me)2, NHCO(CH2)3NCOCH3, NHCOCH2pyridin-2-yl, NHCOCH2(2-aminothiazol-4-yl), NHCOCH2cyclopropyl, NHCO(CH2)2N(Et)2, NHCO(CH2)2(piperazin-2,5-dione-3-yl), NHCOpyrrolidin-1-yl, NHCOmorpholin-4-yl, NHCO2CH2tetrahydrofuran-2-yl, NHCO2tetrahydrofuran-2-yl, NHCO2tetrahydropyran-4-yl, or NHCO2CH2tetrahydropyran-2-yl.
Preferred compounds of formula VI are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R1 is N(R)2, OR, SR, or (T)nxe2x80x94R5;
(b) T is a C1-4 alkylidene chain, wherein one methylene unit of T is optionally replaced by S, O, N(R), or CO2;
(c) R2 is CN, R7, halogen, or N(R6)2;
(d) R3 is a 5-6 membered ring selected from carbocyclic, phenyl, or a heterocyclyl or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R3 is optionally substituted with one (T)nxe2x80x94Ar group and one R7;
(e) Z is a C1-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, NH, NHCO, NHCO2, NHSO2, CONH;
(f) R6 is selected from N(R)2, NHCOR, or Ar wherein Ar is an optionally substituted 5-6 membered heterocyclic or heteroaryl ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
(g) Ra is Rb, ORb, SRb, or N(Rb)2.
More preferred compounds of formula VI are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R1 is selected from SCH2-4-phenol, SCH3, OH, OEt, N(Me)2, OMe, 4-methylpiperidin-1-yl, NHEt, NHCH2CH2piperidin-1-yl, or NHCH2CH2morpholin-4-yl;
(b) R2 is CN;
(c) R3 is a phenyl, pyridyl, furyl, or cyclohexyl ring optionally substituted with (T)nxe2x80x94Ar or R7 wherein Ar is a 5-6 membered aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R7 is selected from R, halogen, OR, N(R)2, or CO2R;
(d) Ra is hydrogen or methyl; and
(e) Zxe2x80x94R6 is selected from O(CH2)3OH, O(CH2)3NH(CH2)2OH, O(CH2)2NH(CH2)2OH, O(CH2)3N(hydroxyethyl) (methyl), O(CH2)3pyrrolidin-1-yl, O(CH2)2morpholin-4-yl, O(CH2)3N(Me)2, O(CH2)3N(Et)2, O(CH2)3(4-hydroxyethylpiperazin-1-yl), O(CH2)3piperazin-1-yl, O(CH2)3(4-hydroxymethylpiperidin-1-yl), O(CH2)3(4-hydroxypiperidin-1-yl), NHCO (CH2)3N(Me)2, NHCO(CH2)3NCOCH3, NHCOCH2pyridin-2-yl, NHCOCH2(2-aminothiazol-4-yl), NHCOCH2cyclopropyl, NHCO(CH2)2N (Et)2, NHCO(CH2)2(piperazin-2,5-dione-3-yl), NHCOpyrrolidin-1-yl, NHCOmorpholin-4-yl, NHCO2CH2tetrahydrofuran-2-yl, NHCO2tetrahydrofuran-2-yl, NHCO2tetrahydropyran-4-yl, or NHCO2CH2tetrahydropyran-2-yl.
Exemplary structures of formula VI are set forth in Table 8 below.
The above formula VI compounds are those having a pyrimidine ring. Compounds of formula VI having a pyridine or triazine ring are otherwise structurally similar to the formula VI compounds and are represented by the following general formulae VII and VIII shown below: 
The compounds of formulae VII and VIII shown above are structurally similar to compounds of formula VI where the pyrimidine ring of formula VI is replaced by a pyridine (VII) or triazine ring (VIII). Accordingly, preferred R1, R2, R3, and Zxe2x80x94R6 groups of the compounds of formulae VII and VIII are as described above for the formula VI compounds.
The present compounds may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I, II, III, IV, V, and VI, and the synthetic examples shown below. 
Scheme I above shows a general synthetic route that is used for preparing the compounds of formula IIa where R2 is CN. These compounds are prepared in a parallel fashion in the following manner. In step (a), xcex1-cyanoacetophenone (1) is combined with K2CO3 (3 equivalents) in DMF and the mixture allowed to stir at room temperature. CS2 (1.5 equivalents) is then added and the resulting mixture stirred at room temperature for an additional 10 minutes. A solution of 1-chloro-propan-2-one (1.0 equivalent) in DMF is added, then a solution of MeI (1.1 equivalents) in DMF is added in a dropwise fashion. After 30 minutes, the mixture is poured onto water and the resulting mixture stirred vigorously for 12-16 hours to afford a suspension of compound 2. The crude product 2 is isolated by filtration. This reaction may be used to obtain compounds of this invention derived from xcex1-cyanoacetophenones having a wide variety of phenyl substituents. Examples of suitable R3 groups include, but are not limited to, those set forth in Table 1 above.
In step (b), the crude product 2 is combined with t-butoxybisdimethylaminomethane (Brederick""s reagent, 3) in THF and allowed to stir at room temperature for 12-16 hours. The reaction mixture is concentrated then used directly for step (c). The crude concentrate 4 is dissolved in EtOH. Compound 5 is added to the ethanolic solution and the resulting mixture heated to 90xc2x0 C. for 4 hours. Although Scheme I uses phenyl guanidine at step (c), it would be obvious to one of skill in the art that other aryl guanidines may be used at step (c) to prepare compounds of the present invention where R4 is a variety of optionally substituted aryl groups. The reaction mixture is concentrated then, after aqueous work-up, the product is purified by preparatory HPLC to afford compounds 6 and 7. The details of the conditions used for producing these compounds are set forth in the Examples. 
Scheme II above shows a general synthetic route that is used for preparing the compounds of formula IIb where R3 is methyl and R4 is an optionally substituted aryl group.
Intermediate 4 is prepared by treating 2,4-pentanedione (1) with potassium carbonate (3 equivalents), CS2 (2) (1.5 equivalents) and chloroacetonitrile (1.0 equivalents) in DMF at room temperature for 2 hours. The mixture is cooled to 0xc2x0 C. then methyl iodide (3) is added slowly and the resulting mixture stirred at room temperature for 12 hours. Water is added to precipitate the product which is isolated by filtration to afford 4.
Intermediate 5 is prepared by treating 4 with dimethylformamide-dimethyl acetal (DMF-DMA) in acetonitrile at reflux for 18 hours. The product 5 is isolated as a yellow solid from trituration with ether.
Compounds of formula IIb are prepared from 5 by combining 5 with an aryl guanidine in acetonitrile and heating the resulting mixture at reflux for 24 hours. Methanol is added to the reaction mixture to precipitate the product and the resulting suspension filterred to afford product IIb. The details of the conditions used for producing these compounds are set forth in the Examples. 
Scheme III above shows a general synthetic route that is used for preparing the compounds of formula IIb where R3 is methyl, R4 is an optionally substituted aryl group, and R2 is 4-methylthiazol-2-yl.
1-[4-Methyl-2-methylsulfanyl-5-(4-methylthiazol-2-yl)-thiophen-3-yl]-ethanone (1) (Maybridge Chemicals) is treated with DMF-DMA in acetonitrile at reflux for 18 hours. The mixture is concentrated in vacuo and the residue triturated with diethyl ether to afford 2 as a yellow solid.
Intermediate 2 is combined with an aryl guanidine in acetonitrile and the resulting mixture heated at reflux for 24 hours. After cooling to room temperature, methanol is added to precipitate the product. The product 3 is isolated by filtration after methanol washes. The details of the conditions used for producing these compounds are set forth in the Examples. 
Using the preparation of compound V-1 as an example, Scheme IV above shows a general synthetic route that may be used to prepare compounds of formula V in parallel fashion in the following manner. In step (a), CS2 is added to a slurry of 3-chlorobenzoylacetonitrile (1) and LiOHxe2x80x94H2O in DMF. The resulting mixture is treated with 1-bromopentan-2-one then to this mixture is then added bromo-Wang resin. The solvent is removed by filtration and the resin rinsed with solvent and dried under nitrogen to afford resin-bound compound 2.
In step (b), compound 2 is combined with THF and DMF-DMA and the resulting slurry heated at 60xc2x0 C. for 18 hours. The solvent is removed by filtration and the resin washed with solvent then dried under nitrogen to afford resin-bound compound 3.
The pyrimidine ring is formed in step (c) by treating 3 with N-phenyl guanidine in THF at reflux for 24 hours. The solvent is removed by filtration and the resin washed several times with solvent. The resulting resin is again treated with N-phenyl guanidine in THF at reflux for another 24 hours. The solvent is again removed by filtration and the resin washed several times with solvent then dried under nitrogen to afford resin-bound compound 4.
The product V-1 is cleaved from the resin in step (d) by treating 4 with trifluoroacetic acid in dichloromethane and water for 3 hours at room temperature. The resin is filtered and washed with dichloromethane then treated with trifluoroacetic acid. The resulting mixture is allowed to sit for 14 hours at room temperature then filtered. The resin is washed with dichloromethane, the solvent concentrated, and the crude product purified by preparative HPLC to afford compound V-1. The details of the conditions used for producing these compounds are set forth in the Examples. 
Scheme V above shows a method for preparing the intermediate compound 5 which may be used to prepare compounds of formulae IIa, IIIa, IVa, V, and VI wherein R3 is a cyclohexyl ring. Intermediate compound 5 may be readily transformed to compounds of formulae IIa, IIIa, IVa, V, and VI by the methods shown in Schemes I-IV above.
In step (a), a solution of ethyl cyanoacetate (2) in acetonitrile is treated with MgCl2 and Et3N at 0xc2x0 C., and the resulting suspension stirred at 0xc2x0 C. for 30 minutes. To this suspension is added cyclohexanecarbonyl chloride (1) and the reaction mixture stirred at 0xc2x0 C. Aqueous workup affords 3. A solution of compound 3 in DMSO/H2O is heated then aqueous work-up affords compound 4.
In step (c), compound 4 may be used to prepare thiophene compound 5 by using the method described in step (a) of Scheme II above. 
Using the preparation of compound VI-18 as an example, Scheme VI above shows a method for preparing compounds of formula VI where R3 is pyridin-3-yl and Z is a C1-4 alkylidene chain wherein one methylene unit of Z is replaced by oxygen.
In step (a), a solution of ethyl nicotinate in toluene is treated with NaH and the resulting suspension heated at 90xc2x0 C. while adding acetonitrile. After heating the reaction overnight, the reaction mixture is allowed to cool and the resulting solids collected by filtration.
Steps (b), (c), and (d) may be performed in a manner substantially similar to those described in step (a) of Scheme II, step (b) of Scheme IV, and step (c) of Schemes I and II. The resulting compound 6 may be used to prepare a variety of compounds of formula VI by using methods known in the art. Compound VI-18 was prepared, via steps (e) through (g), from compound 6 by alkylating the phenol with 3-bromopropanol at step (e). One of skill in the art would recognize that the compound 6 phenol group may be readily derivatized in a number of ways to form other compounds of formula VI. In step (f), the propanol xe2x80x94OH is treated with MsCl to form the mesylate which is displaced with dimethyl amine at step (g) to form compound VI-18. One of skill in the art would recognize that other leaving groups may be utilized to allow for further derivatization of the xe2x80x94OH group and that this leaving group may be displaced with a variety of amines to form other compounds of formula VI. The details of the conditions used to prepared the compounds of Scheme VI are set forth in the Examples. 
Scheme VII above shows a general method for preparing compounds of formula VI where Z is a C1-4 alkylidene chain wherein one methylene unit of Z is replaced by NH or NHCO. Compound 1 may be prepared according to the general methods described above. Compound V-7 may be prepared by steps (a) and (b) according to the methods described above. In step (c), the nitro group is hydrogenated in the presence of palladium on carbon to form the amino compound V-8. Compound V-8 may be used to prepare a variety of compounds of formula VI. For example, compound V-8 may be coupled with a carboxylic acid in order to form amide compounds 5. Alternatively, compound V-8 may be alkylated to form compounds 6. One of skill in the art would recognize that compound V-8 may be treated with a variety of reagents to form other compounds of formula VI.
According to another embodiment, the invention provides a method of inhibiting JNK, Src, or Lck kinase activity in a biological sample. This method comprises the step of contacting said biological sample with a compound of formula I. According to a preferred embodiment, the invention relates to a method of inhibiting JNK, Src, or Lck kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of formula IIa, IIb, V, or VI. A more preferred embodiment relates to contacting said biological sample with a compound of formula IIa or VI.
The term xe2x80x9cbiological samplexe2x80x9d, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
Inhibition of JNK, Src, or Lck kinase activity in a biological sample is useful for a variety of purposes which are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutically acceptable composition. In one embodiment, the composition comprises an amount of compound effective to inhibit a protein kinase, particularly JNK, Src, or Lck, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the compound effective to treat or prevent an JNK, Src, or Lck-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.
The amount effective to inhibit protein kinase, for example, JNK, Src, or Lck, is one that measurably inhibits the kinase activity where compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition.
The term xe2x80x9cpharmaceutically acceptable carrier, adjuvant, or vehiclexe2x80x9d refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
The term xe2x80x9cpatientxe2x80x9d includes human and veterinary subjects.
Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, favoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
According to a preferred embodiment, the pharmaceutical compositions of this invention are orally administered.
According to another embodiment, the present invention relates to a pharmaceutically acceptable derivative of a compound of formula I. In a preferred embodiment, said pharmaceutically acceptable derivative is of a compound of formula IIa, V, or VI. More preferably, said pharmaceutically acceptable derivative is of a preferred compound of formula IIa, V, or VI.
In addition to the compounds of this invention, pharmaceutically acceptable derivatives of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified diseases or disorders.
A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. The methods for preparing salts or esters of a compound of this invention are known to one of skill in the art. Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
Pharmaceutically acceptable derivatives of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+ (C1-4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The dosage of compound will also depend upon which particular compound is in the composition
The compounds of this invention are inhibitors of JNK, Src, or Lck kinase as determined by enzymatic assay. Accordingly, these compounds are useful for treating JNK-, Src-, or Lck-mediated diseases or conditions.
Another aspect of this invention relates to a method for treating a JNK-, Src-, or Lck-mediated disease in a patient, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable composition comprising said compound. According to a preferred embodiment, the invention relates to administering a compound of formula IIa, IIb, IIIa, IIIb, IVa, IVb, V, or VI, or a pharmaceutically acceptable composition comprising said compound. A more preferred embodiment relates to administering a compound of formula IIa, V, or VI, or a pharmaceutically acceptable composition comprising said compound.
Yet another aspect of this invention relates to a method for lessening the severity of a JNK-, Src-, or Lck-mediated disease in a patient, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable composition comprising said compound. According to a preferred embodiment, the invention relates to administering a compound of formula IIa, IIb, IIIa, IIIb, IVa, IVb, V, or VI, or a pharmaceutically acceptable composition comprising said compound. A more preferred embodiment relates to administering a compound of formula IIa, V, or VI, or a pharmaceutically acceptable composition comprising said compound.
The activity of the compounds of this invention as kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of activated enzyme, for example JNK, Lck, or Src. Alternate in vitro assays quantitate the ability of the inhibitor to bind to JNK, Lck, or Src and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/JNK, inhibitor/Lck, or inhibitor/Src complex and determining the amount of radiolabel bound, or by running a competition experiment where new compounds are incubated with JNK, Lck, or Src bound to known radioligands. One may use any type or isoform of JNK, Lck, or Src, depending upon which JNK, Lck, or Src type or isoform is to be inhibited. The details of the conditions used for the enzymatic assays are set forth in the Examples hereinbelow.
The term xe2x80x9cJNK-mediated diseasexe2x80x9d or xe2x80x9cconditionxe2x80x9d, as used herein means any disease or other deleterious condition in which JNK is known to play a role. Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, cancer, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase synthase-2.
Inflammatory diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome.
Autoimmune diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves"" disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn""s disease, psoriasis, or graft vs. host disease.
Destructive bone disorders which may be treated or prevented by the compounds of this invention include, but are not limited to, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.
Proliferative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi""s sarcoma, multiple myeloma and HTLV-1 mediated tumorigenesis.
Angiogenic disorders which may be treated or prevented by the compounds of this invention include solid tumors, ocular neovasculization, infantile haemangiomas. Infectious diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, sepsis, septic shock, and Shigellosis.
Viral diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis.
Neurodegenerative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington""s disease, traumatic brain injury, ischemic and hemorrhaging stroke, cerebral ischemias or neurodegenerative disease, including apoptosis-driven neurodegenerative disease, caused by traumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity.
xe2x80x9cJNK-mediated diseasexe2x80x9d or xe2x80x9cconditionxe2x80x9d also includes ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease, congestive heart failure, pathologic immune responses such as that caused by T cell activation and thrombin-induced platelet aggregation.
In addition, JNK inhibitors of the present invention may be capable of inhibiting the expression of inducible pro-inflammatory proteins. Therefore, other xe2x80x9cJNK-mediated diseasesxe2x80x9d or xe2x80x9cconditionsxe2x80x9d which may be treated by the compounds of this invention include edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.
The compounds of this invention are also useful as inhibitors of Src-family kinases, especially Src. For a general review of these kinases see Thomas and Brugge, Annu. Rev. Cell Dev. Biol. (1997) 13, 513; Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49. Accordingly, these compounds are useful for treating Src-mediated diseases or conditions.
The term xe2x80x9cSrc-mediated diseasexe2x80x9d or xe2x80x9cconditionxe2x80x9d as used herein means any disease or other deleterious condition that is known to be affected by the activity of one or more Src-family kinases. Such diseases or conditions include hypercalcemia, restenosis, hypercalcemia, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft vs. host disease, T-Cell mediated hypersensitivity disease, Hashimoto""s thyroiditis, Guillain-Barre syndrome, chronic obtructive pulmonary disorder, contact dermatitis, cancer, Paget""s disease, asthma, ischemic or reperfusion injury, allergic disease, atopic dermatitis, and allergic rhinitis. Diseases that are affected by Src activity, in particular, include hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget""s disease.
The term xe2x80x9cLck-mediated diseasexe2x80x9d or xe2x80x9cconditionxe2x80x9d as used herein means any disease or other deleterious condition that is known to be affected by the activity of Lck kinase. Such diseases or conditions include autoimmune diseases, allergies, rheumatoid arthritis, and leukemia.
A preferred embodiment relates to the method used to treat or prevent a JNK-mediated disease selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, or thrombin-induced platelet aggregation.
Another preferred embodiment relates to the method used to treat or prevent a Src-mediated disease selected from hypercalcemia, osteoperosis, osteoarthritis, or sympomatic treatment of bone metastasis.
Another preferred embodiment relates to the method used to treat or prevent a Lck-mediated disease selected from autoimmune diseases, rheumatoid arthritis, and leukemia.
Depending upon the particular protein kinase-mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the compounds of this invention. For example, in the treatment of cancer other chemotherapeutic or anti-proliferative agents may be combined with the compounds of this invention to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
Other examples of agents the compounds of this invention may also be combined with include, without limitation, anti-diabetic agents including insulin or insulin analogues in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureaschemotherapeutic agents; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
Those additional agents may be administered separately from the compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
The amount of both, the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above)) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of a compound of formula I can be administered.
In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01-100 xcexcg/kg body weight/day of the additional therapeutic agent can be administered.
The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention.
Each of the aforementioned methods directed to the inhibition of JNK, Lck, or Src, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula I, IIa, V, or VI, as described above. More preferably, each of the aforementioned methods is carried out with a preferred compound of formula I, IIa, V, or VI, and most preferably with a compound of formula IIa, V, or VI.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.